Neuroimaging Technology in Exercise Neurorehabilitation Research in Persons with MS: A Scoping Review

There is increasing interest in the application of neuroimaging technology in exercise neurorehabilitation research among persons with multiple sclerosis (MS). The inclusion and focus on neuroimaging outcomes in MS exercise training research is critical for establishing a biological basis for improvements in functioning and elevating exercise within the neurologist’s clinical armamentarium alongside disease modifying therapies as an approach for treating the disease and its consequences. Indeed, the inclusion of selective neuroimaging approaches and sensor-based technology among physical activity, mobility, and balance outcomes in such MS research might further allow for detecting specific links between the brain and real-world behavior. This paper provided a scoping review on the application of neuroimaging in exercise training research among persons with MS based on searches conducted in PubMed, Web of Science, and Scopus. We identified 60 studies on neuroimaging-technology-based (primarily MRI, which involved a variety of sequences and approaches) correlates of functions, based on multiple sensor-based measures, which are typically targets for exercise training trials in MS. We further identified 12 randomized controlled trials of exercise training effects on neuroimaging outcomes in MS. Overall, there was a large degree of heterogeneity whereby we could not identify definitive conclusions regarding a consistent neuroimaging biomarker of MS-related dysfunction or singular sensor-based measure, or consistent neural adaptation for exercise training in MS. Nevertheless, the present review provides a first step for better linking correlational and randomized controlled trial research for the development of high-quality exercise training studies on the brain in persons with MS, and this is timely given the substantial interest in exercise as a potential disease-modifying and/or neuroplasticity-inducing behavior in this population.


Introduction
Multiple sclerosis is a common neurological disorder that affects upwards of 1 million adults in the United States and 2.5 million adults worldwide [1]. The disease is characterized by inflammatory processes and multifocal demyelination, followed by transection of axons and neurodegeneration [2]. Current recommendations regarding the diagnosis of MS involve establishing dissemination of MS lesions in time and in space based on technology such as 1.5 T or 3 T magnetic resonance imaging (MRI) [3]. Over time, such central nervous system (CNS) damage results in the accumulation of neurological disability and dysfunction, including physiological deconditioning, mobility disability, balance impairment, and cognitive dysfunction. To date, disease-modifying therapies (DMTs) represent first-line treatments for MS and are highly effective for arresting the disease processes and preventing relapses; DMTs are further associated with preservation of brain volume and reduction in lesion burden over the long-term [4]. Phase-III trials support the benefits of DMTs on the disease process and whole-brain neuroimaging metrics, yet such treatments are ineffectual for restoring functions that are compromised by the MS disease processes. This highlights the importance of considering other approaches for restoring functions that are affected by the disease. One such approach involves exercise training, which (as a form of neurorehabilitation) has been suggested to be the best, and perhaps only way to restore function in MS [5].
Exercise training is a powerful neurorehabilitative approach for restoring functions among persons with MS based on a wealth of evidence supporting its multi-systemic beneficial effects on physical activity/physical fitness, mobility, balance, and perhaps cognitive functioning [6]. Such evidence is largely based on exercise training effects on neuroperformance outcomes. By comparison, there is substantially less evidence supporting the effects of exercise training on MRI outcomes in persons with MS, yet this is necessary for establishing exercise training as a neuroplasticity-inducing or neuroprotective behavior [6,7] within the paradigm of neurorehabilitation. Indeed, the inclusion of selective neuroimaging approaches and sensor-based technology among physical activity, mobility, and balance outcomes in such MS research might further allow for detecting specific links between the brain and real-world behavior. Such research is critical for establishing a biological basis for improvements in functioning [6] and elevating exercise within the neurologist's clinical armamentarium alongside DMTs as an approach for treating the disease and its consequences [8,9].
Given the increased interest in the application of neuroimaging in MS exercise research, the time is ripe to provide a scoping review on this topic as an initial effort to identify available evidence, fieldwide limitations, and provide insight on potential approaches for strengthening the field. To that end, the current paper provides a scoping review on the application of neuroimaging in exercise training research among persons with MS based on searches conducted in PubMed, Web of Science, and Scopus. Scoping reviews provide a broad overview of the available research and compile the main sources and types of evidence available, whereas systematic reviews produce a summary of the efficacy or effectiveness of a given intervention based on a precise set of outcomes [10]. This is important as the drive toward evidence-based practice has accelerated, and new approaches toward evidence synthesis, such as scoping reviews, have emerged in recent years for informing clinical research and practice in chronic diseases and conditions [11]. As depicted in Figure 1, this paper first discusses evidence on the current application of MRI for examining neural correlates of functions that are common targets of exercise training (i.e., physical activity/physical fitness, mobility, and balance). This includes MRI techniques from multiple modalities that address CNS structure (i.e., volumetrics, structural connectivity) and function (i.e., activation, functional/effective connectivity). Notably, although cognitive performance represents a target of exercise training trials in MS [12,13], we do not discuss evidence on neural correlates of cognition in MS for this paper based on a prospective scoping review. As such, the topic has been extensively reviewed [14,15]. This paper next discusses the current application of MRI for capturing neuroimaging outcomes from randomized controlled trials (RCTs) of exercise training in persons with MS. Finally, this paper identifies potential future directions for researchers interested in applying neuroimaging within MS-related exercise research. Such future directions are informed by the evidence on neural correlates of functioning, evidence on neuroimaging outcomes from RCTs of exercise training, and the intersection of the aforementioned correlational and RCT research among persons with MS.

Neural Correlates of Functions Targeted in Exercise Training Research in MS
There is an emerging corpus of evidence linking neuroimaging outcomes with functional outcomes among persons with MS. Such research underlies the identification of neural targets that might be central for exercise training-related improvements in functions, as well as for developing neurophysiological hypotheses for why and how specific exercise training approaches might induce specific functional adaptations in persons with MS [16]. Such research might further determine prognostic values of neuroimaging outcomes for predicting functional status in MS [17,18]. Using such observational evidence for hypothesis development and subsequent RCT design might be advantageous for steering clear of a generalized search for neural signals within exercise training research that involves neuroimaging in MS [19].

Neural Correlates of Functions Targeted in Exercise Training Research in MS
There is an emerging corpus of evidence linking neuroimaging outcomes with functional outcomes among persons with MS. Such research underlies the identification of neural targets that might be central for exercise training-related improvements in functions, as well as for developing neurophysiological hypotheses for why and how specific exercise training approaches might induce specific functional adaptations in persons with MS [16]. Such research might further determine prognostic values of neuroimaging outcomes for predicting functional status in MS [17,18]. Using such observational evidence for hypothesis development and subsequent RCT design might be advantageous for steering clear of a generalized search for neural signals within exercise training research that involves neuroimaging in MS [19].

ROI: Hippocampus
When controlling for covariates, engaging in more physical activity was associated with greater RSFC between the hippocampus and posteromedial cortex.
No associations between physical activity and hippocampal RSFC with other regions. Whole-brain and hippocampal volumes were significantly larger in highly active vs. inactive/moderately active groups; thalamic volume not significantly different between groups.
Regarding the results from the 15 studies, higher levels of aerobic power, muscle strength, and physical activity were associated with better neuroimaging outcomes (i.e., higher volumes, lower WM lesion burden, greater connectivity/less diffusivity), yet there was heterogeneity in the results, as some studies reported no significant associations among neuroimaging and physical fitness/physical activity outcomes and some results seemingly conflict. For example, two studies reported that better cardiorespiratory fitness based on VO 2peak was not associated with higher thalamic volume in persons with MS [22,25]. Yet, one recent study reported a significant association between higher thalamic volume and better cardiorespiratory fitness (based on peak work rate) in MS [24]. This suggests that perhaps the consideration of thalamic volume as a neuroimaging correlate of cardiorespiratory fitness depends upon the specific fitness outcome. Indeed, peak work rate has been hypothesized to better reflect cognitive-motor coupling than VO 2peak in this population [24]. Nevertheless, the substantial heterogeneity in neuroimaging modalities/outcome measures and physical fitness/physical activity outcome measures renders the generation of strong conclusions regarding consistent neuroimaging correlates of physical fitness/physical activity in MS difficult.
Neuroimaging Correlates of Mobility in MS. Our PubMed, Web of Science, and Scopus searches identified 30 studies that have examined the association among neuroimaging and mobility outcomes in persons with MS; the studies [23,24,27, are summarized in Table 2. Overall, the majority of studies (26/30) used MRI as the primary imaging modality; 3 studies used fNIRS, and 1 study used EEG as the primary imaging modality. Of the 26 studies that adopted MRI paradigms, there was substantial heterogeneity in the specific MRI outcomes. For example, 21 of the 26 studies reported volumetric outcomes, 10 reported WM lesion burden, 9 reported structural connectivity based on diffusion-weighted imaging, and 3 reported RSFC based on fMRI, along with various other approaches (i.e., magnetic resonance spectroscopy, magnetization transfer imaging, BOLD activation during an ankle flexion task, etc.).     Structural imaging measures of SMA interhemispheric connectivity (AD, RD, MD, but not FA) were significantly related to dual-task walking variability.
Regarding the results, better mobility tended to be associated with better neuroimaging outcomes (i.e., larger volumes, lower WM lesion burden, better structural connectivity, etc.) in persons with MS, yet the pattern of results was heterogenous. Several studies reported no significant associations among neuroimaging and mobility outcomes [23,37,49,61], while some studies reported concurrent associations among specific neuroimaging and mobility outcomes along with no associations among other neuroimaging and mobility outcomes [35,38,39,45,46,[50][51][52]54], as well as cases wherein separate studies reported opposing results [23,24]. Further, there was minimal replication of results such that multiple studies reported different findings using different methodological approaches. As such, the substantial heterogeneity in neuroimaging modalities/outcome measures and mobility outcome measures renders the generation of strong conclusions regarding consistent neuroimaging correlates of mobility in MS difficult.

ROI: Cerebellar peduncles
Higher FA in inferior cerebellar peduncles was associated with shorter path length during the proprioceptive-based mCTSIB condition.
Higher middle cerebellar peduncle RD was associated with longer path length and smaller root mean square of sway during the visual-based balance condition of mCTSIB.
Higher inferior cerebellar peduncle RD was associated with longer path length in the vestibular-based balance condition.

ROI: Cerebellum Spinal cord
When controlling for covariates, higher infratentorial WM lesion burden, lower whole-brain FA, and lower total WM volume significantly predicted greater COP sway.
Regarding the results, better balance was associated with better neuroimaging outcomes (i.e., better structural connectivity, lower WM lesion burden, larger volumes, better functional connectivity, etc.) in persons with MS. One noticeable trend was that studies that adopted diffusion-weighted imaging paradigms consistently reported significant associations of better structural connectivity within cerebellar regions (i.e., peduncles, lobules) with better balance (i.e., lower COP sway, better dynamic balance) [60,[62][63][64]67,69]. Nevertheless, there was still substantial heterogeneity within this area based on a proportion of studies reporting null or conflicting results [61,68,71], as well as differing patterns of selectivity/generality of associations among MRI and balance outcomes [66,70]. Notably, one study did report no associations among cerebellar DTI outcomes and balance outcomes in MS [61]. Collectively, as is the case for the other functional targets of exercise training interventions, it is difficult to generate strong conclusions on neuroimaging correlates of balance in MS, although structural connectivity within cerebellar WM circuits represents a particularly interesting candidate.
Neuroimaging Correlates of Cognition in MS. As described earlier, the neuroimaging correlates of cognition in MS have been extensively reviewed [14,15]. Briefly, numerous MRI metrics that are indicative of disease-related damage to CNS structure and function have been linked with cognitive performance outcomes. For example, white matter lesion burden, poor structural connectivity based on DTI, subcortical deep grey matter atrophy, cortical atrophy, and poor resting-state functional connectivity are associated with impairments in cognitive processing speed, learning and memory, and executive functioning in persons with MS [15]. Further, there have been recent hypotheses regarding impairment of neural network dynamics as an underlying cause of MS-related cognitive dysfunction [72]. However, MRI outcomes do not completely predict cognitive impairment in MS, though grey matter atrophy has emerged as the strongest predictor to date [15].

Neuroimaging Outcomes from Exercise Training RCTs in MS
Our PubMed, Web of Science, and Scopus searches identified 14 papers involving RCTs of exercise training effects on neuroimaging outcomes in persons with MS [23,[73][74][75][76][77][78][79][80][81][82][83][84][85]; the studies are summarized in Table 4. Notably, there were two instances of secondary analyses from original RCTs [75,79]; thus, study results from those secondary analyses are combined with results from the original RCTs in Table 4. As a result, we summarize findings across 12 RCTs. We further note the publication of four non-RCT studies that evaluated the effects of exercise training on neuroimaging outcomes in persons with MS [86][87][88][89]; those studies have been reviewed elsewhere [90].  Exercise was associated with improvements in lower extremity muscular strength, T25FW performance relative to control.
Exercise-related increases in cortical thickness of anterior cingular sulcus and gyrus associated with improvements in lower extremity muscular strength. Both groups demonstrated changes in RSFC, activation during dorsiflexion task, and improvements in 2MW and BBS performance, but between-group differences were not reported.
No association among changes in task-related activation and functional outcomes; other correlations among changes not reported. No other between-group differences in whole-brain volume, subcortical volumes, structural connectivity outcomes, or hippocampal/DMN RSFC.
Exercise training was associated with improved cardiorespiratory fitness, lower extremity muscular strength, and 10/36 SPART performance relative to control.
Improvements in 10/36 SPART performance was associated with increased hippocampal-DMN RSFC in the exercise condition. Node connectivity metrics (i.e., hub disruption index)

ROI: N/A
Functional outcomes data reported in a larger sample in primary analysis paper No between-group changes in total brain volume, WM lesion burden, or clustering coefficient and node path length.
Exercise training was associated with topology-independent (i.e., no significant effect based on hub/non-hub) increases in functional and structural connectivity metrics.
No associations among exercise-related changes in functional and structural connectivity outcomes.
Savsek  Peak work rate

Mobility: 6MW
Other outcomes reported in a secondary paper No difference in percent brain volume change.
Exercise-related improvements in cardiorespiratory fitness.
No significant changes in MRI, cortical thickness, or DKI variables after Bonferroni correction. Non-significant interaction on hippocampal RSFC using seed-based approach.
Large, time x condition interaction on hippocampal-DMN RSFC using independent components analysis approach; exercise associated with reduced RSFC relative to control condition. Other outcomes reported in a secondary paper Exercise training associated with increase in VO 2peak .
No between-group difference for PBVC or BPF or any regional volumes.
Exercise was associated with decreased MD in the thalamus, pallidum, CST, and cingulate gyrus relative to control. PBVC, WM lesion burden, and insula volume did not differ between conditions.
Aerobic exercise training was associated with increases in grey matter volume in frontotemporal regions and decreased grey matter volume in parieto-occipital regions compared with active control.
The results are mixed from RCTs regarding exercise training effects on neuroimaging outcomes in persons with MS. This is largely based on the heterogeneity of experimental design, participant characteristics, exercise prescription parameters, along with neuroimaging modalities and outcomes (Table 4). One consistent pattern of results from the RCTs is that exercise training was generally not associated with improvements in whole-brain level volumetric and lesion-related outcomes relative to control conditions [23,[76][77][78][79]81,82,85]. However, some RCTs did report exercise-related changes on selective neuroimaging outcomes within specific ROIs [23,[73][74][75][76][77][78][79][83][84][85], and others did not [76][77][78][79][80]82,85]. Such selective exercise-related adaptations were inconsistent from study to study and occurred across different imaging outcomes (i.e., volumetrics, structural connectivity/integrity, cortical thickness, resting-state functional connectivity) and regions (i.e., cortex, subcortical deep grey matter structures, resting-state neural networks), whereby there was no robust pattern of results or consistent exercise-related adaptation that was replicated across trials. Moreover, there was no obvious trend regarding RCT results based on MS clinical course, disability status, or associations among changes in neuroimaging and functional outcomes. Thus, as was generally the case for neuroimaging correlates of functioning, it is difficult to render strong conclusions regarding the effects of exercise training on neuroimaging outcomes in persons with MS.

Discussion/Future Directions
The initial purpose of the present scoping review was to first identify available evidence on the increasing interest in the application of neuroimaging technology in exercise research in persons with MS. Such interest was evidenced by the recent proliferation of studies of neuroimaging correlates of functioning as well as RCTs of exercise training on neuroimaging outcomes that were identified based on our PubMed, Web of Science, and Scopus searches. Our scoping review then sought to identify potential fieldwide limitations in this area. Overall, there was substantial heterogeneity associated with the correlational and RCT evidence on neuroimaging correlates of function in MS and exercise training effects on neuroimaging outcomes in MS, respectively. Within the correlational research, there was not a consistent neuroimaging outcome that could be considered as a potential biomarker for MS-related dysfunction based on consistent associations across domains of function or consistent associations with a singular sensor-based measure. There were, however, correlations among selective neuroimaging outcomes and functional outcomes in persons with MS that were inconsistent from study to study. The overall heterogeneity in results might be a factor of varying methodological approaches; neuroimaging modalities, outcomes, and analyses; functional outcomes; and participant characteristics (i.e., disability status, presence/absence of dysfunction). Collectively, such heterogeneity underscores the importance of replication for better establishing promising associations among neuroimaging and functional outcomes as potential biomarkers of specific MS dysfunction (e.g., walking speed). This represents a major opportunity for strengthening the overall scientific field. Given that a majority of the correlational research has been published in the last 3 years, we acknowledge that the nascence of the field has not permitted such broad-scale replication of effects to date. To better facilitate such replicative research efforts, investigators might pay particular attention to neuroimaging sequences and analytic approaches that are reported in studies as an approach to potentially reduce the aforementioned heterogeneity. This further applies to functional outcomes, given that physical fitness, physical activity, mobility, and balance are not unitary constructs. Nevertheless, future replication efforts in this area might harmonize approaches and thereby promote stronger collaboration among investigators from different laboratory groups, institutions, and countries. Such efforts further could improve the generalizability of results for eventual uptake into clinical practice. Notably, despite the overall heterogeneity, there was some consistency regarding associations among various structural connectivity outcomes of the cerebellum and balance-related outcomes [60,[62][63][64]67,68]. Given this specific pattern of results, focusing on the association amongst cerebellar structural connectivity outcomes and MS-related balance dysfunction represents a particularly attractive target for focal research that aims to establish a potential biomarker for balance dysfunction in MS.
Regarding the RCT evidence, there too was not a singular neuroimaging outcome that was consistently sensitive to the effects of exercise training. There were beneficial effects of different exercise training approaches on selective neuroimaging outcomes that were inconsistent from study to study. This was likely a factor of heterogeneous exercise training interventions; comparison conditions; neuroimaging modalities, outcomes, and analytic approaches; and participant characteristics. Further, such heterogeneity did not permit an evaluation of a potential dose-response effect of exercise training on neuroimaging outcomes in persons with MS. Interestingly, the majority of RCT evidence in persons with MS involved aerobic exercise training, and this is likely based on the much larger volume of evidence of aerobic exercise effects on neural outcomes in older adults from the general population [93]. Despite the overall heterogeneity of RCT results, there were two consistent trends that emerged. First, exercise training was generally not associated with changes on whole-brain volumetric outcomes (i.e., percent brain volume change) and WM lesion burden. Second, of the studies that reported exercise-related improvements on neuroimaging outcomes, several reported improvements were on functional neuroimaging outcomes [75,78,83,84]. Taken together, this pattern of results aligns with the cognitive rehabilitation literature in persons with MS, whereby different cognitive rehabilitation approaches are consistently associated with functional, but not structural MRI changes in persons with MS [13]. Further, this is consistent with previous hypotheses supporting integrative CNS plasticity based on changes in brain function with exercise training in MS [16], and suggests that future research efforts might focus on functional neuroimaging outcomes, potentially using graph theory-based analytical approaches [94], as potential endpoints in exercise trials that seek to provide a biological basis of exercise effects on functioning in this population.
The present scoping review identified nearly 60 studies on neuroimaging correlates of function (not including cognition), yet only 12 RCTs of exercise training effects on neuroimaging outcomes. We note that many studies examined neural correlates of multiple functional outcomes (i.e., mobility and balance outcomes) in MS, whereby a single study could be included in multiple categories (i.e., double-counted) within this scoping review [23,24,27,57,60,61]. The discrepancy between correlational and RCT research affords the opportunity to link those categories of research for providing potential future directions for exercise/neuroimaging research in MS. Although correlational research does not allow for the generation of causative inferences, the initial consideration of correlations among variables can inform hypothesis development and features of a subsequent RCT [95]. For example, initial correlations among selective physical fitness and MRI outcomes in MS might lead to hypotheses pertaining to domains of exercise training inducing neural changes in selective ROI among certain MS groups. Such mechanistic hypotheses would presumably inform the target sample, intervention design, MRI outcomes, and functional outcomes for inclusion in a subsequent trial. Such an approach is commonplace in exercise research in older adults from the general population [95], but seemingly less so in MS. Findings from RCT research might alternatively inform the development of observational research that can examine mechanisms associated with demand characteristics from interventions and/or participant characteristics that led to a certain pattern of results [96,97]. For example, an RCT of combined exercise training on grey matter volume in MS might report non-significant results that could be explained by a number of unknown factors (e.g., exercise prescription, target sample/disability status, neuroimaging approach, etc.). Researchers can perform a subsequent cross-sectional study for examining correlations among different domains of fitness (as surrogates for combined exercise training) and neuroimaging outcomes that can lead to new hypotheses and design elements for a subsequent trial that might have a higher likelihood of success. The success of either approach for linking the correlational and RCT evidence in MS likely depends upon strong collaborations among exercise researchers, neuroimaging researchers, neurologists, and other stakeholders involved in comprehensive MS care.
To aid in the facilitation of higher quality exercise/neuroimaging research in MS as in the above examples, we consider the degree to which the correlational evidence maps with that from RCTs as identified in the present scoping review. Overall, there was relatively inconsistent overlap between the correlational studies and RCTs based on large heterogeneity across numerous domains, as outlined above. However, there are several common threads among the correlational and RCT studies. The majority of studies involved MRI as the primary imaging modality. This was unsurprising considering the centrality of MRI in MS differential diagnosis, evaluation of disease progression, and prognosis in clinical practice [3]. Relatedly, regardless of functional outcome or exercise training intervention, volumetric MRI measurements and WM lesion burden were the primary MRI outcomes that were included in the studies. This likely reflects a preponderance of questions regarding the functional consequences of the MS disease process, and the extent to which exercise training can modify disease-related CNS damage, given robust evidence of neuroinflammatory lesions and white and grey matter neurodegeneration with MS. Those outcomes further represent endpoints of clinical trials of DMTs in MS. Despite the commonly included outcomes across correlational and RCT studies, the pattern of results regarding various volumetric and WM lesion-related correlates of different functions in MS did not translate to RCT research. Indeed, there is relatively minimal evidence of exercise-related improvements in whole-brain volume, volumes of subcortical deep grey matter structures, or reductions in WM lesion burden in MS [23,[76][77][78][79]81,82,85]. Collectively, such a pattern of results and associated hypotheses embody the fieldwide consideration of exercise training as a potential disease-modifying behavior in MS [8] as well as other questions regarding the efficacy of exercise training compared with DMT on whole-brain (or perhaps regional) volume and T2 lesion burden endpoints. However, the current evidence base seems insufficient for generating such interferences at present.
The correlational and RCT research less frequently involved diffusion-weighted imaging for evaluating structural integrity of WM tracts and fMRI approaches for measuring resting-state functional connectivity. Notably, the most consistent relationship regarding neural correlates of functioning in MS involved associations among cerebellar structural connectivity metrics with various balance outcomes that were observed in six separate studies [60,[62][63][64]67,69]. By comparison, only one RCT [73] evaluated the effects of balance training on cerebellar neuroimaging outcomes in MS and reported balance-training-related improvements in cerebellar WM integrity that coincided with improvements in balance itself. The relative consistency of correlational research along with the single RCT highlights the importance of future research to focus on balance training as a potential neuroplasticityinducing behavior [90]. Interestingly, several RCTs that reported on significant exerciserelated changes in neuroimaging outcomes involved improvements in RSFC [75,78,83,84]. RSFC has been identified as an outcome that reflects core neuroplastic changes [98], yet is inconsistently correlated with functional outcomes in persons with MS [99]. However, as the understanding of disrupted functional connectivity as a primary consequence of MS improves [72], exercise research might begin to adopt such MRI outcomes more frequently in both correlational and RCT applications. Importantly, the inclusion of neuroimaging outcomes pertaining to both structural and functional connectivity might more closely align with hypotheses that aim to establish a mechanism-of-action associated with MS functional impairments or exercise-related restoration of function. Collectively, such a pattern of results and associated hypotheses embody the fieldwide consideration of exercise training as a potential neuroplasticity-inducing [90] behavior in persons with MS.
Although not necessarily mutually exclusive, the two different hypotheses pertaining to exercise as a disease-modifying and/or neuroplasticity-inducing behavior in MS likely involve different rationales for including selective neuroimaging outcomes. For example, studies that address exercise training as a potential disease-modifying behavior might include neuroimaging outcomes that are FDA-approved endpoints for DMT trials (i.e., whole-brain volume, T2 lesion volume) using conventional MRI approaches. By comparison, studies that address exercise training as a neuroplasticity-inducing behavior in MS might have considerably more freedom to include neuroimaging outcomes that are specific for a hypothesized mechanism of action (e.g., structural connectivity of the cerebellar peduncles). Some studies did not provide any rationale for the inclusion of specific neuroimaging outcomes, or designated neuroimaging outcomes as exploratory. Interestingly, other studies took a middle ground and provided rationale for non-specific ROI based on previous research in non-MS populations (e.g., [85]). As there is no gold-standard for hypothesis development in this area, such overall heterogeneity in hypotheses represents a potential opportunity for RCT researchers to consider the correlational evidence in MS for better characterizing exercise training as both a disease-modifying and neuroplasticityinducing behavior. For example, researchers interested in the hypothesis of aerobic exercise training as a neuroplasticity-inducing behavior in MS might consider specific features of cross-sectional research studies for better developing an RCT. There is cross-sectional evidence that better cardiorespiratory fitness (as a surrogate for aerobic exercise training) is associated with better brain activation during a working memory/processing speed task [20], larger GM volume in midline structures, better regional structural connectivity [21], and larger subcortical deep grey matter volumes [22,24] in persons with relatively mild MS disability. This coincides with other cross-sectional evidence indicating that device-measured ambulatory physical activity is associated with larger subcortical deep grey matter volumes [28,33]. Such cross-sectional evidence might converge with RCT research that focused on walking-based aerobic exercise training (as ambulatory physical activity for improving cardiorespiratory fitness) on structural neuroimaging outcomes involving subcortical deep grey matter structures (i.e., hippocampus) [74,75,84]. Future research efforts might consider such an example when developing subsequent RCTs of exercise training on neuroimaging outcomes in MS.

Conclusions
Collectively, the present scoping review summarized and characterized evidence on neural correlates of function and neuroimaging outcomes in response to exercise training RCTs in persons with MS, with an eye toward informing future research on disease modification and neurorehabilitation. Overall, our PubMed, Web of Science, and Scopus searches yielded a relatively small number of studies, which represents a field-wide limitation. The vast majority of such studies used MRI as the primary neuroimaging outcome, along with neuroperformance measures of physical activity, physical fitness, mobility, balance, and cognition. Overall, there was a large degree of heterogeneity whereby definitive conclusions regarding a consistent neuroimaging biomarker of MS-related dysfunction and consistent neural adaptation to exercise training in MS could not be identified. Such heterogeneity was based on between-study variation in general methodology; neuroimaging modalities, outcomes, and analyses; functional outcomes; and participant characteristics (i.e., disability status, presence/absence of dysfunction). We further note the general lack of replication of results regarding the correlational and RCT evidence. This pattern of heterogeneous results may have been influenced by the small number of studies that were identified by this scoping review, whereby there is not enough research for a definitive convergence of evidence to emerge. Nevertheless, regarding practical implications, the present review provides a first step for better linking correlational and RCT research for the development of high-quality exercise training studies on the brain in persons with MS, given the substantial interest in exercise as a potential disease-modifying and/or neuroplasticity-inducing behavior in this population. Such exercise training studies can study the changes in CNS using existing and new MRI technology, and quantify changes in behavior, physical function, and free-living performance using sensors such as accelerometers, force platforms, and electronic gait mats. Collectively, such research will provide a stronger biological basis for exercise-related changes in functioning among persons with MS.